{"gene":"KIDINS220","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2000,"finding":"Kidins220 was identified as the first physiological substrate of Protein Kinase D (PKD). PKD co-immunoprecipitates and phosphorylates endogenous Kidins220 in PC12 cells. A constitutively active PKD mutant (PKD-S744E/S748E) phosphorylates recombinant Kidins220 in vitro, while a dominant-negative PKD mutant (PKD-D733A) abolishes this phosphorylation. The specific phosphorylation site was mapped to serine 919 within a PKD consensus motif; substitution of S919 to alanine abrogated phosphorylation. Phorbol ester treatment causes specific phosphorylation of S919 in vivo.","method":"Co-immunoprecipitation, in vitro kinase assay with constitutively active and dominant-negative PKD mutants, site-directed mutagenesis (S919A), phospho-specific antibody, phorbol ester stimulation in PC12 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase reconstitution with mutagenesis, reciprocal co-IP, and in vivo phospho-antibody validation in a single rigorous study","pmids":["10998417"],"is_preprint":false},{"year":2000,"finding":"Kidins220 is an integral membrane protein with 11 ankyrin repeats and four transmembrane domains, selectively expressed in brain and neuroendocrine cells, where it concentrates at the tip of neurites.","method":"Cloning, domain analysis, subcellular fractionation, immunocytochemistry in PC12 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with fractionation and immunocytochemistry, single lab","pmids":["10998417"],"is_preprint":false},{"year":2004,"finding":"Kidins220 is constitutively associated with lipid rafts in PC12 cells, primary cortical neurons, and brain synaptosomes. Cholesterol depletion with methyl-β-cyclodextrin alters Kidins220 localization and detergent solubility and delays PKD translocation to lipid raft microdomains. Lipid raft disruption activates PKD and increases Kidins220 phosphorylation on Ser919 via a mechanism involving PKCε and Src kinase.","method":"Sucrose gradient fractionation, immunocytochemistry, confocal microscopy, live-cell GFP-PKD translocation imaging, methyl-β-cyclodextrin cholesterol depletion","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (fractionation, live imaging, pharmacological disruption), single lab","pmids":["15096499"],"is_preprint":false},{"year":2006,"finding":"Kidins220 interacts with the kinesin-1 motor complex via kinesin light chain 1 (KLC1). The interaction was identified by yeast two-hybrid screen and confirmed by GST-pulldown and co-immunoprecipitation. The interaction maps to a short KLC-interacting motif (KIM) in Kidins220 requiring both the TPR and heptad repeat regions of KLC1. Overexpression of KIM in differentiating PC12 cells impairs transport of EGFP-Kidins220 carriers to neurite tips and inhibits NGF-induced MAPK signaling and neurite outgrowth.","method":"Yeast two-hybrid, GST-pulldown, co-immunoprecipitation, live-cell fluorescence imaging, KIM overexpression dominant-negative experiment, MAPK signaling assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — interaction confirmed by three independent methods (Y2H, pulldown, co-IP), functional consequence demonstrated by dominant-negative KIM with multiple readouts","pmids":["17079733"],"is_preprint":false},{"year":2007,"finding":"PKD1, PKD2, and Kidins220 co-exist with neurotensin (NT)-containing vesicles in BON endocrine cells. shRNA-mediated knockdown of Kidins220 inhibits NT secretion. Overexpression of kinase-dead PKD1 abrogates Kidins220 expression and NT vesicle formation, establishing a PKD/Kidins220 pathway in regulation of hormone secretion.","method":"Co-immunoprecipitation, shRNA knockdown, immunofluorescence co-localization, dominant-negative PKD1 overexpression, NT secretion assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus functional knockdown and dominant-negative experiments, single lab","pmids":["18048355"],"is_preprint":false},{"year":2009,"finding":"Kidins220 is downregulated in excitotoxicity via two mechanisms: (1) rapid calpain-mediated cleavage triggered by NR2B-containing NMDAR overactivation and Ca2+ influx, and (2) calpain-independent transcriptional silencing of the Kidins220/Arms gene. Kidins220 forms a complex with NMDARs. Kidins220 knockdown decreases ERK activation and basal neuronal viability, and enhances neuronal death under excitotoxic conditions.","method":"Co-immunoprecipitation (Kidins220-NMDAR association), calpain inhibitor experiments, Ca2+ chelation, shRNA knockdown, ERK phosphorylation assay, neuronal viability assay, in vivo cerebral ischemia model","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, pharmacological dissection of two mechanistic arms, functional knockdown with multiple readouts, replicated in in vivo ischemia model","pmids":["19759287"],"is_preprint":false},{"year":2009,"finding":"Kidins220 modulates neuronal polarity and dendritic development by interacting with tubulin and microtubule-regulating proteins including MAP1a, MAP1b, MAP2, and two stathmin family members. Knockdown of Kidins220 results in multiple axon-like extensions and aberrant dendritic arbors, and alters phosphorylation of MAP1b and stathmins.","method":"Co-immunoprecipitation (Kidins220 with tubulin and MAPs), shRNA knockdown and overexpression in hippocampal neurons, phosphorylation assays, immunocytochemistry","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for binding partners, loss- and gain-of-function experiments with defined morphological and biochemical phenotypes, single lab","pmids":["19903810"],"is_preprint":false},{"year":2009,"finding":"ARMS/Kidins220 regulates dendritic arbor complexity and spine stability in vivo. In ARMS/Kidins220(+/-) mice, dendritic complexity decreases in young adults (not adolescents), and the rate of cortical spine elimination is elevated at 1 month of age, indicating a role in stabilization rather than initial formation of dendritic structures.","method":"In vivo two-photon imaging of cortical spines, Golgi staining of dendritic arbors in heterozygous knockout mice","journal":"Developmental neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vivo imaging with genetic loss-of-function model, single lab","pmids":["19449316"],"is_preprint":false},{"year":2010,"finding":"Kidins220 directly interacts with the RhoGEF Trio through the N-terminus of Trio and the ankyrin repeats of Kidins220. Trio and Kidins220 co-localize at neurite tips in NGF-differentiated PC12 cells along with F-actin and Rac1. Expression of the ankyrin repeats of Kidins220 (dominant negative) inhibits NGF-dependent and Trio-induced neurite outgrowth in PC12 cells and primary hippocampal neurons, placing Kidins220 upstream of Rac1 activation in neurite extension.","method":"Co-immunoprecipitation, GST-pulldown (direct interaction), co-localization by confocal microscopy, dominant-negative ankyrin repeat overexpression, neurite outgrowth assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct interaction confirmed by pulldown and co-IP, epistasis established by dominant-negative approach, multiple cell systems tested","pmids":["20519585"],"is_preprint":false},{"year":2010,"finding":"ARMS/Kidins220 levels regulate basal synaptic transmission in hippocampal neurons. Decreased ARMS/Kidins220 in vivo increased basal synaptic transmission without affecting paired-pulse facilitation. ARMS/Kidins220 interacts with the AMPA receptor subunit GluA1 by co-immunoprecipitation, and modulates GluA1 phosphorylation and cell-surface localization. ARMS/Kidins220 acts as a negative regulator of AMPAR function as shown by inward rectification assays.","method":"Electrophysiology (field recordings in hippocampal slices), co-immunoprecipitation (Kidins220-GluA1), shRNA knockdown, cell-surface biotinylation, inward rectification assay","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, shRNA, biotinylation, and electrophysiology in a single study, single lab","pmids":["20547223"],"is_preprint":false},{"year":2010,"finding":"ARMS/Kidins220 is cleaved by calpain in an activity-dependent manner following KCl depolarization in hippocampal neurons. ARMS/Kidins220(+/-) mice exhibit enhanced long-term potentiation, and calpain inhibition reverses this effect, indicating that calpain-mediated proteolysis of ARMS/Kidins220 regulates synaptic plasticity.","method":"KCl depolarization of hippocampal neurons, calpain inhibitor experiments, LTP recordings in hippocampal slices from heterozygous knockout mice","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological epistasis with electrophysiological readout, single lab","pmids":["20943655"],"is_preprint":false},{"year":2011,"finding":"Kidins220 constitutively interacts with VEGFR2 and mediates VEGF signaling. Kidins220(-/-) embryos display cardiovascular abnormalities and extensive neuronal apoptosis. Primary neurons from Kidins220(-/-) mice show reduced MAPK signaling, neurite outgrowth, and potentiation of excitatory postsynaptic currents in response to BDNF.","method":"Co-immunoprecipitation (Kidins220-VEGFR2), full knockout mouse phenotyping, MAPK phosphorylation assay in primary neurons, whole-cell electrophysiology, neurite outgrowth assay","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — constitutive co-IP of Kidins220-VEGFR2, knockout phenotype with multiple orthogonal cellular and electrophysiological readouts","pmids":["22048155"],"is_preprint":false},{"year":2011,"finding":"Kidins220 is required for heart outflow tract and ventricle wall development, and for peripheral nervous system (DRG) survival. Neuronal-specific deletion of Kidins220 leads to early postnatal death. Kidins220 functions as a membrane-anchored scaffold for neurotrophin receptors TrkA/B/C and p75NTR.","method":"Full and conditional knockout mouse histology, apoptosis assays (TUNEL), immunohistochemistry for Trk and p75NTR","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with detailed histological and molecular phenotyping, single lab","pmids":["22048169"],"is_preprint":false},{"year":2012,"finding":"Kidins220 accumulates with hyperphosphorylated tau in Alzheimer's disease brains. GSK3β phosphorylation of Kidins220 decreases its susceptibility to calpain-mediated proteolysis, while PP1 action has the opposite effect, establishing a GSK3β/PP1 imbalance as a mechanism controlling Kidins220 clearance in neurodegeneration.","method":"Immunoprecipitation and immunoblotting in AD brain necropsies and GSK3β-transgenic mice, in vitro calpain proteolysis assays, kinase/phosphatase treatment experiments","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro calpain assay combined with post-translational modification mapping in disease tissue and transgenic model, single lab","pmids":["23118350"],"is_preprint":false},{"year":2012,"finding":"Kidins220/ARMS is a novel modulator of short-term synaptic plasticity specifically in GABAergic neurons. In Kidins220(-/-) hippocampal neurons, the slow recovery from synaptic depression of inhibitory postsynaptic currents is strongly reduced. This phenotype is explained by absence of a transient reduction in vesicle release probability that occurs in wild-type GABAergic synapses.","method":"Whole-cell patch-clamp recordings (paired-pulse and train stimulation protocols) in Kidins220 full knockout hippocampal cultures","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout model with detailed electrophysiological analysis, single lab","pmids":["22563401"],"is_preprint":false},{"year":2012,"finding":"ARMS/Kidins220 knockdown impairs dendritic branching in mouse cerebral cortex in vivo and reduces dendritic length, number, and complexity in primary hippocampal neurons. Overexpression of TrkB or EphB2 in ARMS/Kidins220-deficient neurons partially rescues dendritic defects. PI3K/Akt signaling is a key downstream pathway; loss of ARMS/Kidins220 reduces EphB2 receptor signaling complex clustering.","method":"In utero electroporation for in vivo knockdown, shRNA in primary neurons, TrkB/EphB2 overexpression rescue, PI3K/Akt inhibitors, receptor clustering assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo and in vitro loss-of-function with receptor overexpression rescue, pathway placement via PI3K/Akt, multiple orthogonal readouts","pmids":["22699907"],"is_preprint":false},{"year":2013,"finding":"Kidins220 associates with the pre-TCR, αβTCR, and γδTCR, and with B-Raf. Kidins220 is required for TCR-induced sustained (but not transient) Erk activation and optimal calcium signaling. Upon prolonged TCR stimulation, the Kidins220-TCR interaction decreases. Loss of Kidins220 blocks induction of c-Fos and Egr-1 and reduces CD69, IL-2, and IFN-γ upregulation, placing Kidins220 as a coupler of B-Raf to the TCR for sustained Erk signaling.","method":"Mass spectrometry identification of B-Raf interaction, co-immunoprecipitation, proximity ligation assay, shRNA knockdown in T cell lines, intracellular calcium imaging, ERK phosphorylation time-course assays, cytokine measurement","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS identification confirmed by co-IP and PLA, functional knockdown with multiple downstream readouts establishing pathway position, single lab but multiple orthogonal methods","pmids":["23359496"],"is_preprint":false},{"year":2015,"finding":"The major calpain cleavage site in Kidins220 was mapped to between amino acids 1669 and 1670 in a highly conserved C-terminal sequence. A cell-penetrating peptide (Tat-K) encompassing this site (aa 1668–1681) reduces Kidins220 calpain processing dose- and time-dependently after excitotoxic insult, preserves pERK1/2 and pCREB activity, and increases neuronal viability.","method":"In vitro and in vivo calpain cleavage assays with deletion/truncation mapping, cell-penetrating peptide transduction, ERK and CREB phosphorylation assays, neuronal viability assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro cleavage mapping plus functional peptide rescue with multiple signaling readouts, single lab","pmids":["26492372"],"is_preprint":false},{"year":2015,"finding":"Kidins220 associates with brain voltage-gated sodium channels (Nav) as shown by co-immunoprecipitation. Kidins220 ablation increases excitability of hippocampal GABAergic neurons, increases sodium conductance, and alters Nav current kinetics and voltage dependence in HEK293 cells co-transfected with Nav channels, placing Kidins220 as a modulator of Nav channel activity.","method":"Co-immunoprecipitation (Kidins220-Nav), multielectrode array recordings, current-clamp recordings, patch-clamp Nav current recordings in HEK293 cells, in silico neuronal model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — co-IP interaction confirmed, functional consequences demonstrated in both knockout neurons and heterologous expression system, complemented by computational model","pmids":["26037926"],"is_preprint":false},{"year":2015,"finding":"Kidins220/ARMS binds to the B cell antigen receptor (BCR) complex in both resting and stimulated states; upon BCR stimulation, this interaction increases in a Src kinase-independent manner. Kidins220 couples the BCR to PLCγ2, Ca2+, and ERK signaling. Conditional B cell-specific knockout (B-KO) shows impaired pre-BCR and BCR signaling, reduced B cell activation, and a sixfold reduction in λ light chain-positive B cells, genetically placing Kidins220 in the PLCγ2 pathway.","method":"Mass spectrometry identification, co-immunoprecipitation, conditional knockout mouse (B cell-specific Cre), PLCγ2/Ca2+/ERK signaling assays, B cell development FACS analysis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-identified interaction confirmed by co-IP, conditional knockout with genetic epistasis placing Kidins220 in PLCγ2 pathway, multiple orthogonal methods","pmids":["26324445"],"is_preprint":false},{"year":2018,"finding":"ARMS/Kidins220 negatively regulates regulated BDNF secretion in neurons. Downregulation of ARMS/Kidins220 in adult mouse brain increases BDNF secretion and striatal BDNF accumulation. In two mouse models of Huntington's disease, ARMS/Kidins220 is elevated in the hippocampus and regulated BDNF secretion is impaired; reducing ARMS/Kidins220 reverses this defect. ARMS/Kidins220 regulates Synaptotagmin-IV (Syt-IV) levels, which modulates BDNF secretion.","method":"Conditional mouse knockout for ARMS/Kidins220, BDNF secretion assays in neurons and hippocampal slices, Syt-IV protein level measurement, HD transgenic mouse models, human HD brain immunoblotting","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional mouse model with functional secretion assay and disease model rescue, mechanistic link to Syt-IV identified but not deeply validated, single lab","pmids":["29769266"],"is_preprint":false},{"year":2019,"finding":"Kidins220 ablation in astrocytes causes defects in Ca2+ signaling linked to altered store-operated Ca2+ entry and strong overexpression of the TRPV4 channel. Kidins220-/- astrocytes are more sensitive to genotoxic stress. Kidins220 expression in astrocytes is required for proper connectivity of co-cultured wild-type neurons.","method":"Ca2+ imaging in primary astrocyte cultures (Kidins220 knockout), TRPV4 immunoblotting and immunofluorescence, genotoxic stress assays, neuronal co-culture connectivity analysis","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout model with direct Ca2+ imaging and mechanistic link to TRPV4 upregulation plus functional co-culture assay, single lab","pmids":["31624352"],"is_preprint":false},{"year":2021,"finding":"Kidins220 deficiency causes ventriculomegaly via downregulation of the SNX27-retromer complex, which leads to lysosomal degradation of AQP4 (aquaporin-4). AQP4 was identified as a novel cargo of the SNX27-retromer. Kidins220 deficient mice show loss of AQP4 at ventricular ependyma and in astrocytes. SNX27 silencing decreases AQP4 levels; SNX27 overexpression restores AQP4 in Kidins220-deficient astrocytes, establishing the KIDINS220-SNX27-retromer-AQP4 pathway.","method":"Kidins220 knockout mouse phenotyping, AQP4 immunofluorescence, SNX27-retromer interaction assays, lysosome inhibition experiments, SNX27 knockdown and overexpression in astrocytes, iNPH patient brain tissue immunostaining","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Strong — pathway mechanistically dissected through knockout, SNX27 knockdown/rescue experiments, lysosomal inhibition, and human patient tissue, multiple orthogonal methods","pmids":["34002021"],"is_preprint":false},{"year":2021,"finding":"A novel homozygous in-frame deletion mutation in KIDINS220 adjacent to the fourth transmembrane domain diminishes binding of KIDINS220 to TrkA, as demonstrated by co-immunoprecipitation. This reduced TrkA interaction is associated with fetal brain ventriculomegaly and limb contractures, implicating TrkA as a likely mediator of the KIDINS220 loss-of-function phenotype.","method":"Co-immunoprecipitation of mutant vs wild-type KIDINS220 with TrkA, fetal brain autopsy/imaging, exome sequencing","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP demonstrating reduced TrkA binding by mutation, supported by human genetic evidence, single lab","pmids":["33205811"],"is_preprint":false},{"year":2022,"finding":"XPR1 (phosphate exporter) requires KIDINS220 as a novel partner protein for proper cellular localization and activity. Disruption of the XPR1-KIDINS220 complex by genetic or pharmacologic inhibition of XPR1 in SLC34A2-high cancer cell lines results in toxic intracellular phosphate accumulation and formation of acidic vacuolar structures preceding cell death.","method":"CRISPR-Cas9 loss-of-function screens, cellular localization assays, phosphate efflux assays, vacuolar morphology imaging, XPR1 genetic/pharmacologic inhibition in cancer cell lines and in vivo xenograft models","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional complex established in genome-scale screens and validated by mechanistic localization and phosphate efflux assays in vitro and in vivo","pmids":["35437317"],"is_preprint":false},{"year":2004,"finding":"Kidins220 is expressed in immature dendritic cells (DC), where it localizes at the leading edge membrane protrusion in a lipid raft compartment. F-actin co-localizes with Kidins220 at the leading edge and is required for its polarized membrane localization. Disruption of lipid rafts with methyl-β-cyclodextrin causes loss of Kidins220 polarization, cell rounding, and inhibition of DC motility.","method":"Immunocytochemistry, confocal microscopy, methyl-β-cyclodextrin raft disruption, F-actin depolymerization, motility assays in monocyte-derived and peripheral blood DC","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence (motility inhibition upon raft disruption), single lab","pmids":["14971036"],"is_preprint":false}],"current_model":"Kidins220/ARMS is a conserved integral transmembrane scaffold protein primarily expressed in neurons that functions as a PKD substrate (phosphorylated at S919 by PKD), a kinesin-1/KLC1-dependent cargo for axonal transport, and a convergence platform for neurotrophin (Trk/p75NTR), VEGFR2, ephrin, NMDAR, AMPAR, TCR, BCR, and voltage-gated sodium channel signaling; it promotes neuronal survival, polarity, dendrite complexity, and spine stability by organizing Trio/Rac1, PI3K/Akt, MAPK/ERK, and PLCγ2/Ca2+ pathways, while being negatively regulated by calpain cleavage during synaptic activity and excitotoxicity; it also forms a complex with XPR1 to control cellular phosphate homeostasis and with SNX27-retromer to maintain AQP4 at the ependymal surface and regulate CSF homeostasis."},"narrative":{"mechanistic_narrative":"Kidins220 (kinase D-interacting substrate of 220 kDa, also called ARMS) is an integral membrane scaffold protein, concentrated at neurite tips and lipid raft microdomains, that organizes multiple receptor signaling pathways to control neuronal survival, polarity, and synaptic function [PMID:10998417, PMID:15096499]. It was first defined as the principal physiological substrate of Protein Kinase D, which phosphorylates it on Ser919 within a PKD consensus motif [PMID:10998417]. Kidins220 is delivered to neurite tips as a kinesin-1 cargo through a KLC1-interacting motif, a transport step required for NGF-induced MAPK signaling and neurite outgrowth [PMID:17079733]. As a membrane-anchored platform for the neurotrophin receptors TrkA/B/C and p75NTR and for VEGFR2, it couples these receptors to MAPK/ERK and PI3K/Akt signaling, and its loss in mice produces cardiovascular defects, neuronal apoptosis, and early postnatal death [PMID:22048155, PMID:22048169]. Kidins220 promotes neurite extension by binding the RhoGEF Trio through its ankyrin repeats to drive Rac1 activation [PMID:20519585], and shapes dendritic arbor complexity and spine stability via TrkB/EphB2 receptor clustering and downstream PI3K/Akt signaling [PMID:19449316, PMID:22699907]. At synapses it interacts with the NMDAR, AMPAR subunit GluA1, and voltage-gated sodium channels to tune excitatory transmission, plasticity, and excitability [PMID:19759287, PMID:20547223, PMID:26037926], and it negatively regulates BDNF secretion through control of Synaptotagmin-IV [PMID:29769266]. Kidins220 is negatively regulated by activity-dependent calpain cleavage downstream of NMDAR overactivation, with the major cut site mapped between residues 1669 and 1670; this proteolysis governs synaptic plasticity and neuronal viability during excitotoxicity and is modulated by a GSK3β/PP1 phosphorylation balance [PMID:19759287, PMID:20943655, PMID:23118350, PMID:26492372]. Beyond the nervous system, Kidins220 couples antigen receptors to downstream signaling—linking the TCR to B-Raf for sustained ERK activation and the BCR to PLCγ2/Ca2+/ERK [PMID:23359496, PMID:26324445]—and acts as an obligate partner of the phosphate exporter XPR1 to maintain phosphate homeostasis [PMID:35437317] and of the SNX27-retromer to preserve surface AQP4 and CSF homeostasis [PMID:34002021]. A homozygous in-frame KIDINS220 deletion that weakens TrkA binding causes fetal ventriculomegaly with limb contractures, establishing a Mendelian disease link [PMID:33205811].","teleology":[{"year":2000,"claim":"Established Kidins220's founding biochemical identity by showing it is the first physiological PKD substrate, defining a specific regulated phosphorylation event (Ser919) that links it to PKD signaling.","evidence":"Co-IP, in vitro kinase assays with constitutively active/dominant-negative PKD, S919A mutagenesis, and phospho-specific antibody in PC12 cells","pmids":["10998417"],"confidence":"High","gaps":["Functional consequence of S919 phosphorylation on scaffold behavior not resolved","Domain analysis (11 ankyrin repeats, 4 TM domains) descriptive, not functionally dissected"]},{"year":2004,"claim":"Connected Kidins220 localization to lipid raft microdomains and showed raft integrity governs its PKD-dependent phosphorylation and its polarized membrane positioning in motile cells.","evidence":"Sucrose gradient fractionation, live GFP-PKD imaging, methyl-β-cyclodextrin raft disruption in neurons; immunocytochemistry and motility assays in dendritic cells","pmids":["15096499","14971036"],"confidence":"Medium","gaps":["Molecular basis of raft targeting not defined","Link between raft localization and downstream scaffold output incomplete"]},{"year":2006,"claim":"Explained how Kidins220 reaches its functional site by identifying it as a KLC1-dependent kinesin-1 cargo, coupling axonal transport to NGF-MAPK signaling and neurite outgrowth.","evidence":"Yeast two-hybrid, GST-pulldown, co-IP, live imaging, and dominant-negative KIM overexpression in PC12 cells","pmids":["17079733"],"confidence":"High","gaps":["Regulation of cargo loading/unloading unknown","Whether transport is activity- or phosphorylation-dependent untested"]},{"year":2009,"claim":"Defined Kidins220 as a cytoskeletal and GEF-linked organizer of neuronal polarity, binding tubulin/MAPs and the RhoGEF Trio to drive Rac1-dependent neurite extension and proper axon/dendrite specification.","evidence":"Co-IP, GST-pulldown, shRNA/overexpression in hippocampal neurons, dominant-negative ankyrin-repeat experiments, neurite outgrowth assays","pmids":["19903810","20519585"],"confidence":"High","gaps":["How Trio activity is regulated within the complex not resolved","Direct effect on microtubule dynamics inferred from phosphorylation changes only"]},{"year":2009,"claim":"Established Kidins220 as an NMDAR-associated survival factor that is selectively degraded during excitotoxicity through calpain cleavage and transcriptional silencing.","evidence":"Co-IP, calpain inhibitor and Ca2+ chelation experiments, shRNA, ERK and viability assays, in vivo ischemia model","pmids":["19759287"],"confidence":"High","gaps":["Calpain cleavage site not yet mapped at this stage","Mechanism of transcriptional silencing unknown"]},{"year":2009,"claim":"Demonstrated in vivo that Kidins220 stabilizes (rather than forms) dendritic arbors and cortical spines, distinguishing a maintenance role.","evidence":"Two-photon imaging and Golgi staining in heterozygous knockout mice","pmids":["19449316"],"confidence":"Medium","gaps":["Molecular effectors of spine stabilization not identified here","Heterozygous model may underrepresent full loss"]},{"year":2010,"claim":"Positioned Kidins220 as a regulator of synaptic transmission and plasticity, negatively modulating AMPAR (GluA1) function and tuning LTP through calpain-mediated activity-dependent proteolysis.","evidence":"Electrophysiology in hippocampal slices, co-IP with GluA1, surface biotinylation, KCl depolarization with calpain inhibition in knockout mice","pmids":["20547223","20943655"],"confidence":"Medium","gaps":["Direct vs indirect effect on GluA1 trafficking unresolved","Calpain site still unmapped at this point"]},{"year":2011,"claim":"Defined Kidins220 as an essential scaffold for VEGFR2 and neurotrophin (Trk/p75NTR) receptors in vivo, required for cardiovascular development and central/peripheral neuronal survival.","evidence":"Co-IP, full and conditional knockout mouse phenotyping, MAPK assays, electrophysiology, TUNEL and IHC","pmids":["22048155","22048169"],"confidence":"High","gaps":["Receptor-specific contributions to lethality not separated","Stoichiometry of multi-receptor scaffolding unknown"]},{"year":2012,"claim":"Extended Kidins220's synaptic role to GABAergic short-term plasticity and inhibitory transmission and linked its calpain clearance to a GSK3β/PP1 balance relevant to Alzheimer pathology.","evidence":"Patch-clamp in knockout cultures; immunoblotting in AD brain and GSK3β-transgenic mice with in vitro calpain proteolysis assays","pmids":["22563401","23118350"],"confidence":"Medium","gaps":["GABAergic vesicle-release mechanism downstream of Kidins220 not defined","AD association correlative, not causal"]},{"year":2013,"claim":"Showed Kidins220 also controls dendritic branching via PI3K/Akt downstream of TrkB and EphB2, with receptor overexpression rescuing loss-of-function defects.","evidence":"In utero electroporation, shRNA, TrkB/EphB2 rescue, PI3K/Akt inhibitors, receptor clustering assays","pmids":["22699907"],"confidence":"High","gaps":["How Kidins220 promotes EphB2 complex clustering mechanistically unclear"]},{"year":2015,"claim":"Mapped the major calpain cleavage site (aa 1669/1670) and used a protective peptide to validate that blocking cleavage preserves ERK/CREB signaling and neuronal viability; concurrently identified Kidins220 as a modulator of Nav channels.","evidence":"Cleavage mapping with truncations, Tat-K cell-penetrating peptide rescue; co-IP with Nav and patch-clamp in knockout neurons and HEK293","pmids":["26492372","26037926"],"confidence":"High","gaps":["Whether Nav modulation is direct or scaffold-mediated unresolved","Therapeutic translatability of protective peptide untested in vivo broadly"]},{"year":2013,"claim":"Extended Kidins220 scaffolding to immune receptor signaling, coupling the TCR to B-Raf for sustained ERK activation.","evidence":"Mass spectrometry, co-IP, proximity ligation, shRNA in T cell lines, Ca2+ imaging, ERK time-course, cytokine readouts","pmids":["23359496"],"confidence":"High","gaps":["Mechanism distinguishing sustained vs transient ERK coupling not fully defined"]},{"year":2015,"claim":"Established Kidins220 as a BCR-associated scaffold coupling antigen receptor engagement to PLCγ2/Ca2+/ERK and required for normal B cell development.","evidence":"Mass spectrometry, co-IP, B cell-specific conditional knockout, PLCγ2/Ca2+/ERK assays, FACS","pmids":["26324445"],"confidence":"High","gaps":["Direct binding interface with BCR components not mapped","Src-independent recruitment mechanism unexplained"]},{"year":2018,"claim":"Identified a presynaptic-secretory role: Kidins220 negatively regulates regulated BDNF secretion via Synaptotagmin-IV, with relevance to Huntington's disease BDNF deficits.","evidence":"Conditional knockout, BDNF secretion assays, Syt-IV measurement, HD mouse models and human HD brain immunoblotting","pmids":["29769266"],"confidence":"Medium","gaps":["Mechanism linking Kidins220 to Syt-IV levels not deeply validated"]},{"year":2019,"claim":"Revealed a glial function: Kidins220 in astrocytes maintains Ca2+ signaling (store-operated entry, TRPV4 levels), stress resistance, and supports neuronal connectivity.","evidence":"Ca2+ imaging, TRPV4 immunoblotting/IF, genotoxic stress assays, and neuron co-culture in knockout astrocytes","pmids":["31624352"],"confidence":"Medium","gaps":["Mechanism of TRPV4 overexpression upon Kidins220 loss unknown","Direct Ca2+-channel partners in astrocytes not identified"]},{"year":2021,"claim":"Defined two non-neuronal scaffold functions and a human disease link: Kidins220 maintains surface AQP4 via the SNX27-retromer to control CSF/ventricular homeostasis, and a TrkA-binding-deficient KIDINS220 deletion causes fetal ventriculomegaly with limb contractures.","evidence":"Knockout mouse phenotyping, SNX27 knockdown/rescue, lysosomal inhibition, patient tissue; 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divergent arms of the antiviral response in the duplicated genomes of salmonid fishes.","date":"2023","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/37286012","citation_count":16,"is_preprint":false},{"pmid":"32708976","id":"PMC_32708976","title":"Brothers in Arms: Structure, Assembly and Function of Arenaviridae Nucleoprotein.","date":"2020","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/32708976","citation_count":15,"is_preprint":false},{"pmid":"33205811","id":"PMC_33205811","title":"TrkA mediates effect of novel KIDINS220 mutation in human brain ventriculomegaly.","date":"2021","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33205811","citation_count":15,"is_preprint":false},{"pmid":"32002282","id":"PMC_32002282","title":"Calreticulin arms NK cells against 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one","url":"https://pubmed.ncbi.nlm.nih.gov/22563401","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":40896,"output_tokens":7392,"usd":0.116784,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16752,"output_tokens":5732,"usd":0.11353,"stage2_stop_reason":"end_turn"},"total_usd":0.230314,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"Kidins220 was identified as the first physiological substrate of Protein Kinase D (PKD). PKD co-immunoprecipitates and phosphorylates endogenous Kidins220 in PC12 cells. A constitutively active PKD mutant (PKD-S744E/S748E) phosphorylates recombinant Kidins220 in vitro, while a dominant-negative PKD mutant (PKD-D733A) abolishes this phosphorylation. The specific phosphorylation site was mapped to serine 919 within a PKD consensus motif; substitution of S919 to alanine abrogated phosphorylation. Phorbol ester treatment causes specific phosphorylation of S919 in vivo.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay with constitutively active and dominant-negative PKD mutants, site-directed mutagenesis (S919A), phospho-specific antibody, phorbol ester stimulation in PC12 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase reconstitution with mutagenesis, reciprocal co-IP, and in vivo phospho-antibody validation in a single rigorous study\",\n      \"pmids\": [\"10998417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Kidins220 is an integral membrane protein with 11 ankyrin repeats and four transmembrane domains, selectively expressed in brain and neuroendocrine cells, where it concentrates at the tip of neurites.\",\n      \"method\": \"Cloning, domain analysis, subcellular fractionation, immunocytochemistry in PC12 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with fractionation and immunocytochemistry, single lab\",\n      \"pmids\": [\"10998417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Kidins220 is constitutively associated with lipid rafts in PC12 cells, primary cortical neurons, and brain synaptosomes. Cholesterol depletion with methyl-β-cyclodextrin alters Kidins220 localization and detergent solubility and delays PKD translocation to lipid raft microdomains. Lipid raft disruption activates PKD and increases Kidins220 phosphorylation on Ser919 via a mechanism involving PKCε and Src kinase.\",\n      \"method\": \"Sucrose gradient fractionation, immunocytochemistry, confocal microscopy, live-cell GFP-PKD translocation imaging, methyl-β-cyclodextrin cholesterol depletion\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (fractionation, live imaging, pharmacological disruption), single lab\",\n      \"pmids\": [\"15096499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Kidins220 interacts with the kinesin-1 motor complex via kinesin light chain 1 (KLC1). The interaction was identified by yeast two-hybrid screen and confirmed by GST-pulldown and co-immunoprecipitation. The interaction maps to a short KLC-interacting motif (KIM) in Kidins220 requiring both the TPR and heptad repeat regions of KLC1. Overexpression of KIM in differentiating PC12 cells impairs transport of EGFP-Kidins220 carriers to neurite tips and inhibits NGF-induced MAPK signaling and neurite outgrowth.\",\n      \"method\": \"Yeast two-hybrid, GST-pulldown, co-immunoprecipitation, live-cell fluorescence imaging, KIM overexpression dominant-negative experiment, MAPK signaling assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — interaction confirmed by three independent methods (Y2H, pulldown, co-IP), functional consequence demonstrated by dominant-negative KIM with multiple readouts\",\n      \"pmids\": [\"17079733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PKD1, PKD2, and Kidins220 co-exist with neurotensin (NT)-containing vesicles in BON endocrine cells. shRNA-mediated knockdown of Kidins220 inhibits NT secretion. Overexpression of kinase-dead PKD1 abrogates Kidins220 expression and NT vesicle formation, establishing a PKD/Kidins220 pathway in regulation of hormone secretion.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, immunofluorescence co-localization, dominant-negative PKD1 overexpression, NT secretion assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus functional knockdown and dominant-negative experiments, single lab\",\n      \"pmids\": [\"18048355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Kidins220 is downregulated in excitotoxicity via two mechanisms: (1) rapid calpain-mediated cleavage triggered by NR2B-containing NMDAR overactivation and Ca2+ influx, and (2) calpain-independent transcriptional silencing of the Kidins220/Arms gene. Kidins220 forms a complex with NMDARs. Kidins220 knockdown decreases ERK activation and basal neuronal viability, and enhances neuronal death under excitotoxic conditions.\",\n      \"method\": \"Co-immunoprecipitation (Kidins220-NMDAR association), calpain inhibitor experiments, Ca2+ chelation, shRNA knockdown, ERK phosphorylation assay, neuronal viability assay, in vivo cerebral ischemia model\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, pharmacological dissection of two mechanistic arms, functional knockdown with multiple readouts, replicated in in vivo ischemia model\",\n      \"pmids\": [\"19759287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Kidins220 modulates neuronal polarity and dendritic development by interacting with tubulin and microtubule-regulating proteins including MAP1a, MAP1b, MAP2, and two stathmin family members. Knockdown of Kidins220 results in multiple axon-like extensions and aberrant dendritic arbors, and alters phosphorylation of MAP1b and stathmins.\",\n      \"method\": \"Co-immunoprecipitation (Kidins220 with tubulin and MAPs), shRNA knockdown and overexpression in hippocampal neurons, phosphorylation assays, immunocytochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for binding partners, loss- and gain-of-function experiments with defined morphological and biochemical phenotypes, single lab\",\n      \"pmids\": [\"19903810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ARMS/Kidins220 regulates dendritic arbor complexity and spine stability in vivo. In ARMS/Kidins220(+/-) mice, dendritic complexity decreases in young adults (not adolescents), and the rate of cortical spine elimination is elevated at 1 month of age, indicating a role in stabilization rather than initial formation of dendritic structures.\",\n      \"method\": \"In vivo two-photon imaging of cortical spines, Golgi staining of dendritic arbors in heterozygous knockout mice\",\n      \"journal\": \"Developmental neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vivo imaging with genetic loss-of-function model, single lab\",\n      \"pmids\": [\"19449316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Kidins220 directly interacts with the RhoGEF Trio through the N-terminus of Trio and the ankyrin repeats of Kidins220. Trio and Kidins220 co-localize at neurite tips in NGF-differentiated PC12 cells along with F-actin and Rac1. Expression of the ankyrin repeats of Kidins220 (dominant negative) inhibits NGF-dependent and Trio-induced neurite outgrowth in PC12 cells and primary hippocampal neurons, placing Kidins220 upstream of Rac1 activation in neurite extension.\",\n      \"method\": \"Co-immunoprecipitation, GST-pulldown (direct interaction), co-localization by confocal microscopy, dominant-negative ankyrin repeat overexpression, neurite outgrowth assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct interaction confirmed by pulldown and co-IP, epistasis established by dominant-negative approach, multiple cell systems tested\",\n      \"pmids\": [\"20519585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ARMS/Kidins220 levels regulate basal synaptic transmission in hippocampal neurons. Decreased ARMS/Kidins220 in vivo increased basal synaptic transmission without affecting paired-pulse facilitation. ARMS/Kidins220 interacts with the AMPA receptor subunit GluA1 by co-immunoprecipitation, and modulates GluA1 phosphorylation and cell-surface localization. ARMS/Kidins220 acts as a negative regulator of AMPAR function as shown by inward rectification assays.\",\n      \"method\": \"Electrophysiology (field recordings in hippocampal slices), co-immunoprecipitation (Kidins220-GluA1), shRNA knockdown, cell-surface biotinylation, inward rectification assay\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, shRNA, biotinylation, and electrophysiology in a single study, single lab\",\n      \"pmids\": [\"20547223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ARMS/Kidins220 is cleaved by calpain in an activity-dependent manner following KCl depolarization in hippocampal neurons. ARMS/Kidins220(+/-) mice exhibit enhanced long-term potentiation, and calpain inhibition reverses this effect, indicating that calpain-mediated proteolysis of ARMS/Kidins220 regulates synaptic plasticity.\",\n      \"method\": \"KCl depolarization of hippocampal neurons, calpain inhibitor experiments, LTP recordings in hippocampal slices from heterozygous knockout mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological epistasis with electrophysiological readout, single lab\",\n      \"pmids\": [\"20943655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Kidins220 constitutively interacts with VEGFR2 and mediates VEGF signaling. Kidins220(-/-) embryos display cardiovascular abnormalities and extensive neuronal apoptosis. Primary neurons from Kidins220(-/-) mice show reduced MAPK signaling, neurite outgrowth, and potentiation of excitatory postsynaptic currents in response to BDNF.\",\n      \"method\": \"Co-immunoprecipitation (Kidins220-VEGFR2), full knockout mouse phenotyping, MAPK phosphorylation assay in primary neurons, whole-cell electrophysiology, neurite outgrowth assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — constitutive co-IP of Kidins220-VEGFR2, knockout phenotype with multiple orthogonal cellular and electrophysiological readouts\",\n      \"pmids\": [\"22048155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Kidins220 is required for heart outflow tract and ventricle wall development, and for peripheral nervous system (DRG) survival. Neuronal-specific deletion of Kidins220 leads to early postnatal death. Kidins220 functions as a membrane-anchored scaffold for neurotrophin receptors TrkA/B/C and p75NTR.\",\n      \"method\": \"Full and conditional knockout mouse histology, apoptosis assays (TUNEL), immunohistochemistry for Trk and p75NTR\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with detailed histological and molecular phenotyping, single lab\",\n      \"pmids\": [\"22048169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Kidins220 accumulates with hyperphosphorylated tau in Alzheimer's disease brains. GSK3β phosphorylation of Kidins220 decreases its susceptibility to calpain-mediated proteolysis, while PP1 action has the opposite effect, establishing a GSK3β/PP1 imbalance as a mechanism controlling Kidins220 clearance in neurodegeneration.\",\n      \"method\": \"Immunoprecipitation and immunoblotting in AD brain necropsies and GSK3β-transgenic mice, in vitro calpain proteolysis assays, kinase/phosphatase treatment experiments\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro calpain assay combined with post-translational modification mapping in disease tissue and transgenic model, single lab\",\n      \"pmids\": [\"23118350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Kidins220/ARMS is a novel modulator of short-term synaptic plasticity specifically in GABAergic neurons. In Kidins220(-/-) hippocampal neurons, the slow recovery from synaptic depression of inhibitory postsynaptic currents is strongly reduced. This phenotype is explained by absence of a transient reduction in vesicle release probability that occurs in wild-type GABAergic synapses.\",\n      \"method\": \"Whole-cell patch-clamp recordings (paired-pulse and train stimulation protocols) in Kidins220 full knockout hippocampal cultures\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout model with detailed electrophysiological analysis, single lab\",\n      \"pmids\": [\"22563401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ARMS/Kidins220 knockdown impairs dendritic branching in mouse cerebral cortex in vivo and reduces dendritic length, number, and complexity in primary hippocampal neurons. Overexpression of TrkB or EphB2 in ARMS/Kidins220-deficient neurons partially rescues dendritic defects. PI3K/Akt signaling is a key downstream pathway; loss of ARMS/Kidins220 reduces EphB2 receptor signaling complex clustering.\",\n      \"method\": \"In utero electroporation for in vivo knockdown, shRNA in primary neurons, TrkB/EphB2 overexpression rescue, PI3K/Akt inhibitors, receptor clustering assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo and in vitro loss-of-function with receptor overexpression rescue, pathway placement via PI3K/Akt, multiple orthogonal readouts\",\n      \"pmids\": [\"22699907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Kidins220 associates with the pre-TCR, αβTCR, and γδTCR, and with B-Raf. Kidins220 is required for TCR-induced sustained (but not transient) Erk activation and optimal calcium signaling. Upon prolonged TCR stimulation, the Kidins220-TCR interaction decreases. Loss of Kidins220 blocks induction of c-Fos and Egr-1 and reduces CD69, IL-2, and IFN-γ upregulation, placing Kidins220 as a coupler of B-Raf to the TCR for sustained Erk signaling.\",\n      \"method\": \"Mass spectrometry identification of B-Raf interaction, co-immunoprecipitation, proximity ligation assay, shRNA knockdown in T cell lines, intracellular calcium imaging, ERK phosphorylation time-course assays, cytokine measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS identification confirmed by co-IP and PLA, functional knockdown with multiple downstream readouts establishing pathway position, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"23359496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The major calpain cleavage site in Kidins220 was mapped to between amino acids 1669 and 1670 in a highly conserved C-terminal sequence. A cell-penetrating peptide (Tat-K) encompassing this site (aa 1668–1681) reduces Kidins220 calpain processing dose- and time-dependently after excitotoxic insult, preserves pERK1/2 and pCREB activity, and increases neuronal viability.\",\n      \"method\": \"In vitro and in vivo calpain cleavage assays with deletion/truncation mapping, cell-penetrating peptide transduction, ERK and CREB phosphorylation assays, neuronal viability assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro cleavage mapping plus functional peptide rescue with multiple signaling readouts, single lab\",\n      \"pmids\": [\"26492372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Kidins220 associates with brain voltage-gated sodium channels (Nav) as shown by co-immunoprecipitation. Kidins220 ablation increases excitability of hippocampal GABAergic neurons, increases sodium conductance, and alters Nav current kinetics and voltage dependence in HEK293 cells co-transfected with Nav channels, placing Kidins220 as a modulator of Nav channel activity.\",\n      \"method\": \"Co-immunoprecipitation (Kidins220-Nav), multielectrode array recordings, current-clamp recordings, patch-clamp Nav current recordings in HEK293 cells, in silico neuronal model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — co-IP interaction confirmed, functional consequences demonstrated in both knockout neurons and heterologous expression system, complemented by computational model\",\n      \"pmids\": [\"26037926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Kidins220/ARMS binds to the B cell antigen receptor (BCR) complex in both resting and stimulated states; upon BCR stimulation, this interaction increases in a Src kinase-independent manner. Kidins220 couples the BCR to PLCγ2, Ca2+, and ERK signaling. Conditional B cell-specific knockout (B-KO) shows impaired pre-BCR and BCR signaling, reduced B cell activation, and a sixfold reduction in λ light chain-positive B cells, genetically placing Kidins220 in the PLCγ2 pathway.\",\n      \"method\": \"Mass spectrometry identification, co-immunoprecipitation, conditional knockout mouse (B cell-specific Cre), PLCγ2/Ca2+/ERK signaling assays, B cell development FACS analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-identified interaction confirmed by co-IP, conditional knockout with genetic epistasis placing Kidins220 in PLCγ2 pathway, multiple orthogonal methods\",\n      \"pmids\": [\"26324445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ARMS/Kidins220 negatively regulates regulated BDNF secretion in neurons. Downregulation of ARMS/Kidins220 in adult mouse brain increases BDNF secretion and striatal BDNF accumulation. In two mouse models of Huntington's disease, ARMS/Kidins220 is elevated in the hippocampus and regulated BDNF secretion is impaired; reducing ARMS/Kidins220 reverses this defect. ARMS/Kidins220 regulates Synaptotagmin-IV (Syt-IV) levels, which modulates BDNF secretion.\",\n      \"method\": \"Conditional mouse knockout for ARMS/Kidins220, BDNF secretion assays in neurons and hippocampal slices, Syt-IV protein level measurement, HD transgenic mouse models, human HD brain immunoblotting\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional mouse model with functional secretion assay and disease model rescue, mechanistic link to Syt-IV identified but not deeply validated, single lab\",\n      \"pmids\": [\"29769266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Kidins220 ablation in astrocytes causes defects in Ca2+ signaling linked to altered store-operated Ca2+ entry and strong overexpression of the TRPV4 channel. Kidins220-/- astrocytes are more sensitive to genotoxic stress. Kidins220 expression in astrocytes is required for proper connectivity of co-cultured wild-type neurons.\",\n      \"method\": \"Ca2+ imaging in primary astrocyte cultures (Kidins220 knockout), TRPV4 immunoblotting and immunofluorescence, genotoxic stress assays, neuronal co-culture connectivity analysis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout model with direct Ca2+ imaging and mechanistic link to TRPV4 upregulation plus functional co-culture assay, single lab\",\n      \"pmids\": [\"31624352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Kidins220 deficiency causes ventriculomegaly via downregulation of the SNX27-retromer complex, which leads to lysosomal degradation of AQP4 (aquaporin-4). AQP4 was identified as a novel cargo of the SNX27-retromer. Kidins220 deficient mice show loss of AQP4 at ventricular ependyma and in astrocytes. SNX27 silencing decreases AQP4 levels; SNX27 overexpression restores AQP4 in Kidins220-deficient astrocytes, establishing the KIDINS220-SNX27-retromer-AQP4 pathway.\",\n      \"method\": \"Kidins220 knockout mouse phenotyping, AQP4 immunofluorescence, SNX27-retromer interaction assays, lysosome inhibition experiments, SNX27 knockdown and overexpression in astrocytes, iNPH patient brain tissue immunostaining\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pathway mechanistically dissected through knockout, SNX27 knockdown/rescue experiments, lysosomal inhibition, and human patient tissue, multiple orthogonal methods\",\n      \"pmids\": [\"34002021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A novel homozygous in-frame deletion mutation in KIDINS220 adjacent to the fourth transmembrane domain diminishes binding of KIDINS220 to TrkA, as demonstrated by co-immunoprecipitation. This reduced TrkA interaction is associated with fetal brain ventriculomegaly and limb contractures, implicating TrkA as a likely mediator of the KIDINS220 loss-of-function phenotype.\",\n      \"method\": \"Co-immunoprecipitation of mutant vs wild-type KIDINS220 with TrkA, fetal brain autopsy/imaging, exome sequencing\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP demonstrating reduced TrkA binding by mutation, supported by human genetic evidence, single lab\",\n      \"pmids\": [\"33205811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"XPR1 (phosphate exporter) requires KIDINS220 as a novel partner protein for proper cellular localization and activity. Disruption of the XPR1-KIDINS220 complex by genetic or pharmacologic inhibition of XPR1 in SLC34A2-high cancer cell lines results in toxic intracellular phosphate accumulation and formation of acidic vacuolar structures preceding cell death.\",\n      \"method\": \"CRISPR-Cas9 loss-of-function screens, cellular localization assays, phosphate efflux assays, vacuolar morphology imaging, XPR1 genetic/pharmacologic inhibition in cancer cell lines and in vivo xenograft models\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional complex established in genome-scale screens and validated by mechanistic localization and phosphate efflux assays in vitro and in vivo\",\n      \"pmids\": [\"35437317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Kidins220 is expressed in immature dendritic cells (DC), where it localizes at the leading edge membrane protrusion in a lipid raft compartment. F-actin co-localizes with Kidins220 at the leading edge and is required for its polarized membrane localization. Disruption of lipid rafts with methyl-β-cyclodextrin causes loss of Kidins220 polarization, cell rounding, and inhibition of DC motility.\",\n      \"method\": \"Immunocytochemistry, confocal microscopy, methyl-β-cyclodextrin raft disruption, F-actin depolymerization, motility assays in monocyte-derived and peripheral blood DC\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence (motility inhibition upon raft disruption), single lab\",\n      \"pmids\": [\"14971036\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Kidins220/ARMS is a conserved integral transmembrane scaffold protein primarily expressed in neurons that functions as a PKD substrate (phosphorylated at S919 by PKD), a kinesin-1/KLC1-dependent cargo for axonal transport, and a convergence platform for neurotrophin (Trk/p75NTR), VEGFR2, ephrin, NMDAR, AMPAR, TCR, BCR, and voltage-gated sodium channel signaling; it promotes neuronal survival, polarity, dendrite complexity, and spine stability by organizing Trio/Rac1, PI3K/Akt, MAPK/ERK, and PLCγ2/Ca2+ pathways, while being negatively regulated by calpain cleavage during synaptic activity and excitotoxicity; it also forms a complex with XPR1 to control cellular phosphate homeostasis and with SNX27-retromer to maintain AQP4 at the ependymal surface and regulate CSF homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Kidins220 (kinase D-interacting substrate of 220 kDa, also called ARMS) is an integral membrane scaffold protein, concentrated at neurite tips and lipid raft microdomains, that organizes multiple receptor signaling pathways to control neuronal survival, polarity, and synaptic function [#1, #2]. It was first defined as the principal physiological substrate of Protein Kinase D, which phosphorylates it on Ser919 within a PKD consensus motif [#0]. Kidins220 is delivered to neurite tips as a kinesin-1 cargo through a KLC1-interacting motif, a transport step required for NGF-induced MAPK signaling and neurite outgrowth [#3]. As a membrane-anchored platform for the neurotrophin receptors TrkA/B/C and p75NTR and for VEGFR2, it couples these receptors to MAPK/ERK and PI3K/Akt signaling, and its loss in mice produces cardiovascular defects, neuronal apoptosis, and early postnatal death [#11, #12]. Kidins220 promotes neurite extension by binding the RhoGEF Trio through its ankyrin repeats to drive Rac1 activation [#8], and shapes dendritic arbor complexity and spine stability via TrkB/EphB2 receptor clustering and downstream PI3K/Akt signaling [#7, #15]. At synapses it interacts with the NMDAR, AMPAR subunit GluA1, and voltage-gated sodium channels to tune excitatory transmission, plasticity, and excitability [#5, #9, #18], and it negatively regulates BDNF secretion through control of Synaptotagmin-IV [#20]. Kidins220 is negatively regulated by activity-dependent calpain cleavage downstream of NMDAR overactivation, with the major cut site mapped between residues 1669 and 1670; this proteolysis governs synaptic plasticity and neuronal viability during excitotoxicity and is modulated by a GSK3\\u03b2/PP1 phosphorylation balance [#5, #10, #13, #17]. Beyond the nervous system, Kidins220 couples antigen receptors to downstream signaling—linking the TCR to B-Raf for sustained ERK activation and the BCR to PLC\\u03b32/Ca2+/ERK [#16, #19]—and acts as an obligate partner of the phosphate exporter XPR1 to maintain phosphate homeostasis [#24] and of the SNX27-retromer to preserve surface AQP4 and CSF homeostasis [#22]. A homozygous in-frame KIDINS220 deletion that weakens TrkA binding causes fetal ventriculomegaly with limb contractures, establishing a Mendelian disease link [#23].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established Kidins220's founding biochemical identity by showing it is the first physiological PKD substrate, defining a specific regulated phosphorylation event (Ser919) that links it to PKD signaling.\",\n      \"evidence\": \"Co-IP, in vitro kinase assays with constitutively active/dominant-negative PKD, S919A mutagenesis, and phospho-specific antibody in PC12 cells\",\n      \"pmids\": [\"10998417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of S919 phosphorylation on scaffold behavior not resolved\", \"Domain analysis (11 ankyrin repeats, 4 TM domains) descriptive, not functionally dissected\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Connected Kidins220 localization to lipid raft microdomains and showed raft integrity governs its PKD-dependent phosphorylation and its polarized membrane positioning in motile cells.\",\n      \"evidence\": \"Sucrose gradient fractionation, live GFP-PKD imaging, methyl-\\u03b2-cyclodextrin raft disruption in neurons; immunocytochemistry and motility assays in dendritic cells\",\n      \"pmids\": [\"15096499\", \"14971036\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of raft targeting not defined\", \"Link between raft localization and downstream scaffold output incomplete\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Explained how Kidins220 reaches its functional site by identifying it as a KLC1-dependent kinesin-1 cargo, coupling axonal transport to NGF-MAPK signaling and neurite outgrowth.\",\n      \"evidence\": \"Yeast two-hybrid, GST-pulldown, co-IP, live imaging, and dominant-negative KIM overexpression in PC12 cells\",\n      \"pmids\": [\"17079733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Regulation of cargo loading/unloading unknown\", \"Whether transport is activity- or phosphorylation-dependent untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined Kidins220 as a cytoskeletal and GEF-linked organizer of neuronal polarity, binding tubulin/MAPs and the RhoGEF Trio to drive Rac1-dependent neurite extension and proper axon/dendrite specification.\",\n      \"evidence\": \"Co-IP, GST-pulldown, shRNA/overexpression in hippocampal neurons, dominant-negative ankyrin-repeat experiments, neurite outgrowth assays\",\n      \"pmids\": [\"19903810\", \"20519585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Trio activity is regulated within the complex not resolved\", \"Direct effect on microtubule dynamics inferred from phosphorylation changes only\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established Kidins220 as an NMDAR-associated survival factor that is selectively degraded during excitotoxicity through calpain cleavage and transcriptional silencing.\",\n      \"evidence\": \"Co-IP, calpain inhibitor and Ca2+ chelation experiments, shRNA, ERK and viability assays, in vivo ischemia model\",\n      \"pmids\": [\"19759287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Calpain cleavage site not yet mapped at this stage\", \"Mechanism of transcriptional silencing unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated in vivo that Kidins220 stabilizes (rather than forms) dendritic arbors and cortical spines, distinguishing a maintenance role.\",\n      \"evidence\": \"Two-photon imaging and Golgi staining in heterozygous knockout mice\",\n      \"pmids\": [\"19449316\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular effectors of spine stabilization not identified here\", \"Heterozygous model may underrepresent full loss\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Positioned Kidins220 as a regulator of synaptic transmission and plasticity, negatively modulating AMPAR (GluA1) function and tuning LTP through calpain-mediated activity-dependent proteolysis.\",\n      \"evidence\": \"Electrophysiology in hippocampal slices, co-IP with GluA1, surface biotinylation, KCl depolarization with calpain inhibition in knockout mice\",\n      \"pmids\": [\"20547223\", \"20943655\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect effect on GluA1 trafficking unresolved\", \"Calpain site still unmapped at this point\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined Kidins220 as an essential scaffold for VEGFR2 and neurotrophin (Trk/p75NTR) receptors in vivo, required for cardiovascular development and central/peripheral neuronal survival.\",\n      \"evidence\": \"Co-IP, full and conditional knockout mouse phenotyping, MAPK assays, electrophysiology, TUNEL and IHC\",\n      \"pmids\": [\"22048155\", \"22048169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor-specific contributions to lethality not separated\", \"Stoichiometry of multi-receptor scaffolding unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended Kidins220's synaptic role to GABAergic short-term plasticity and inhibitory transmission and linked its calpain clearance to a GSK3\\u03b2/PP1 balance relevant to Alzheimer pathology.\",\n      \"evidence\": \"Patch-clamp in knockout cultures; immunoblotting in AD brain and GSK3\\u03b2-transgenic mice with in vitro calpain proteolysis assays\",\n      \"pmids\": [\"22563401\", \"23118350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GABAergic vesicle-release mechanism downstream of Kidins220 not defined\", \"AD association correlative, not causal\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed Kidins220 also controls dendritic branching via PI3K/Akt downstream of TrkB and EphB2, with receptor overexpression rescuing loss-of-function defects.\",\n      \"evidence\": \"In utero electroporation, shRNA, TrkB/EphB2 rescue, PI3K/Akt inhibitors, receptor clustering assays\",\n      \"pmids\": [\"22699907\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Kidins220 promotes EphB2 complex clustering mechanistically unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapped the major calpain cleavage site (aa 1669/1670) and used a protective peptide to validate that blocking cleavage preserves ERK/CREB signaling and neuronal viability; concurrently identified Kidins220 as a modulator of Nav channels.\",\n      \"evidence\": \"Cleavage mapping with truncations, Tat-K cell-penetrating peptide rescue; co-IP with Nav and patch-clamp in knockout neurons and HEK293\",\n      \"pmids\": [\"26492372\", \"26037926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Nav modulation is direct or scaffold-mediated unresolved\", \"Therapeutic translatability of protective peptide untested in vivo broadly\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended Kidins220 scaffolding to immune receptor signaling, coupling the TCR to B-Raf for sustained ERK activation.\",\n      \"evidence\": \"Mass spectrometry, co-IP, proximity ligation, shRNA in T cell lines, Ca2+ imaging, ERK time-course, cytokine readouts\",\n      \"pmids\": [\"23359496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism distinguishing sustained vs transient ERK coupling not fully defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established Kidins220 as a BCR-associated scaffold coupling antigen receptor engagement to PLC\\u03b32/Ca2+/ERK and required for normal B cell development.\",\n      \"evidence\": \"Mass spectrometry, co-IP, B cell-specific conditional knockout, PLC\\u03b32/Ca2+/ERK assays, FACS\",\n      \"pmids\": [\"26324445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interface with BCR components not mapped\", \"Src-independent recruitment mechanism unexplained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified a presynaptic-secretory role: Kidins220 negatively regulates regulated BDNF secretion via Synaptotagmin-IV, with relevance to Huntington's disease BDNF deficits.\",\n      \"evidence\": \"Conditional knockout, BDNF secretion assays, Syt-IV measurement, HD mouse models and human HD brain immunoblotting\",\n      \"pmids\": [\"29769266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking Kidins220 to Syt-IV levels not deeply validated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a glial function: Kidins220 in astrocytes maintains Ca2+ signaling (store-operated entry, TRPV4 levels), stress resistance, and supports neuronal connectivity.\",\n      \"evidence\": \"Ca2+ imaging, TRPV4 immunoblotting/IF, genotoxic stress assays, and neuron co-culture in knockout astrocytes\",\n      \"pmids\": [\"31624352\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of TRPV4 overexpression upon Kidins220 loss unknown\", \"Direct Ca2+-channel partners in astrocytes not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined two non-neuronal scaffold functions and a human disease link: Kidins220 maintains surface AQP4 via the SNX27-retromer to control CSF/ventricular homeostasis, and a TrkA-binding-deficient KIDINS220 deletion causes fetal ventriculomegaly with limb contractures.\",\n      \"evidence\": \"Knockout mouse phenotyping, SNX27 knockdown/rescue, lysosomal inhibition, patient tissue; co-IP of mutant vs WT with TrkA, exome sequencing and fetal imaging\",\n      \"pmids\": [\"34002021\", \"33205811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Kidins220 stabilizes SNX27-retromer levels mechanistically unclear\", \"Causality of single human deletion family limited\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established Kidins220 as an obligate partner of the phosphate exporter XPR1, required for XPR1 localization and activity, with therapeutic implications for phosphate-stressed cancers.\",\n      \"evidence\": \"CRISPR loss-of-function screens, localization and phosphate efflux assays, vacuolar imaging, and xenografts\",\n      \"pmids\": [\"35437317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of XPR1-Kidins220 complex not resolved\", \"Whether neuronal Kidins220 roles intersect with phosphate handling unexplored\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single scaffold integrates and prioritizes its many receptor and transporter partners (neurotrophin/VEGFR2, antigen receptors, ion channels, XPR1, SNX27-retromer) in a context-specific manner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of multi-partner assembly\", \"Phosphorylation/proteolysis code that switches between functions not defined\", \"Tissue-specific partner selection unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [11, 12, 16, 19, 24, 22]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 18, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 25]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 8, 11, 15, 16, 19]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [5, 9, 14, 18]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [16, 19]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [24, 22]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 22]}\n    ],\n    \"complexes\": [\"kinesin-1 (KLC1) complex\", \"XPR1-KIDINS220 complex\", \"SNX27-retromer\"],\n    \"partners\": [\"PRKD1\", \"KLC1\", \"TRIO\", \"VEGFR2\", \"NTRK1\", \"XPR1\", \"SNX27\", \"BRAF\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}